This program project brings together an interdisciplinary team of three scientists with unique expertise to functionally target and inhibit human polyomavirus infections. The polyomaviruses in general, and the human polyomaviruses in particular, have been shown to utilize distinct host cell carbohydrates and proteins to infect target cells and tissues. The human polyomavirus JCV is the causative agent of a fatal central nervous system demyelinating disease known as progressive multifocal leukoencephalopathy (PML). The majority of PML cases occur in patients with AIDS but recently PML has also been shown to occur in multiple sclerosis patients being treated with potent immunomodulatory drugs that inhibit immunosurveillance of the CNS. There are currently no drugs in the pipeline that target the virus directly and a major goal of this program is to identify compounds capable of directly inhibiting virus infection. This goal will be accomplished by close collaborative interactions between a team consisting of a polyomavirologist, a structural biologist, and a structural chemist. Project # 1 led by Professor Thilo Stehle will focus on structurally characterizing and identifying sites on the virus that are critical for interacting with host cell surfaces. Project # 2 led by Professor Walter Atwood will introduce site-specific mutations in the virus based on these structures and functionally characterize the mutants for defects in assembly, DNA packaging, cell binding, cell penetration, and infection. Project # 3 led by Professor Dale Mierke will design and synthesize chemical compounds to antagonize virus host cell interactions. These compounds will be functionally screened by Project # 2. The projects will be supported by a chemical synthesis core at Dartmouth College headed by Drs. Mierke and Spaller. An administrative core will be housed at Brown University. The overall goal of this program is to use structural information to derive exquisitely specific inhibitors of polyomavirus infection that are potent, nontoxic, and bioavailable. The three major investigators on the team have built a strong working collaboration that is evidenced by the solid preliminary data supporting this application.